Process for preparation of piperazyl alkyl derivatives of tetrazoles



United States Patent Olfice 3,499,900 PROCESS FOR PREPARATION OF PIPERAZYL ALKYL DERIVATIVES F TETRAZOLES Robert Norman Schut, Edwardsburg, Mich., and Herbert John Havera, Elkhart, Ind., assignors to Miles Laboratories, Inc., Elkhart, Ind., a corporation of Indiana No Drawing. Filed May 3, 1967, Ser. No. 635,699 Int. Cl. C07d 51/70 US. Cl. 260-268 Claims ABSTRACT OF THE DISCLOSURE A process for the synthesis of piperazylalkyl derivatives of tetrazoles having beneficial pharmacological properties. Generally the synthesis involves the acylation of a piperazine with a suitable haloalkanoyl halide, substitution of the resulting w-haloalkanoylpiperazine by cyanide ion, closing of the ring on the resulting w-cyanoamide with azide ion to form an w-tetrazolylarnide and reduction of the amide to the desired amine.

This invention relates to the synthesis of tetrazole derivatives and more particularly to a novel process for the synthesis of piperazylalkyl derivatives of tetrazoles having beneficial pharmacological properties.

Compounds synthesized according to the process of this invention can be represented by means of the structural formula:

in which R represents a member selected from a group consisting of phenyl and substituted phenyl wherein the substituents are selected from the group consisting of chloro, fluoro, and trifluoromethyl and n is an integer between about 1 and 3.

Compounds of this invention can be furnished in forms of various salts, for example, as salts of mineral acids such as hydrochloride, or as salts of organic acids, such as an oxalate or maleate. In general, salts which are pharmacologically acceptable are used. Representative of these compounds, in the form of a salt, is 5-[2-(4-phenyll-piperazyl)ethyl]tetrazole monohydrochloride which has the formula:

The novel piperazylalkyltetrazole derivatives of this invention are useful as anti-hypertensive agents.

In the process of the invention novel oxo compounds are formed having the structural formula:

which are useful as intermediates in the process of the invention.

In US. Patent No. 3,231,574, issued Jan. 25, 1966, to Wallace Glenn Strycker and Shin Hayao and assigned to the instant assignee, a process is described for syn- 3,499,900 Patented Mar. 10, 1970 thesizing tetrazole derivatives corresponding to tetrazole derivatives prepared by the novel process of this invention. Tetrazole derivatives are prepared in US. Patent No. 3,231,574, by reacting the appropriate nitrile with an azide salt of a monovalent' cation. Thus it i necessary to have the appropriate 4-aryl-1-(w-cyanoalkyl) piperazine for conversion to the tetrazole.

Therefore, it is an object of this invention to provide a novel process for synthesizing tetrazole derivatives.

A further object of this invention is to provide a process for synthesizing desirable tetrazole derivatives with readily available reactants which process has satisfactory overall yields.

Other objects and advantages of this invention will become apparent from the following description.

The invention is generally embodied in a process for synthesizing a compound of the structural formula:

in which R and n correspond respectively with their previous description. A compound of this structural formula can be prepared according to the following general reaction sequence.

X and Y are halogen atoms and can be the same or different.

The first step of this reaction sequence is an acylation of a piperazine with a suitable haloalkanoyl halide to form an N-(w-haloalkanoyl) piperazine. In a substitution reaction with cyanide ion, the resulting N-(w-haloalkanoyl) piperazine is converted to an N-(w-cyanoalkanoyl) piperazine. Ring closure is effected by the reacting N-(wcyanoalkanoyl) piperazine with azide ion such as from an azide salt of a monovalent cation or hydrazoic acid- Reduction with LiAlH, produces the desired compound.

More specifically, a piperazine is reacted with a suitable haloalkanoyl halide, preferably a halo acetyl halide, such as chloroacetylchloride. This reaction is carried out in the presence of a base, for example, a hydroxide or carbonate. Sodium hydroxide or sodium carbonate are examples of bases which may be used. Although the conditions of the reaction are not considered critical, the reactants are advantageously mixed slowly while being maintained at a low temperature. A mixing temperature of about 0 C. is considered satisfactory. The resulting solution is preferably stirred for three or more hours while maintaining it at between 0 to 10 C.

The amide resulting from the first step in the reaction sequence is then substituted; with a cyanide ion from a suitable source to form an amide. This cyanide ion source may bean inorganic cyanide compound and is preferably a compound such as sodium cyanide, potassium cyanide, etc. To facilitate the reaction the reactants are generally dissolved in suitable solvents such as methanol and water, respectively. The reactants are heated and beneficially maintained under reflux in excess of 4 hours.

CHC13 max.

1660 cm.- (amide carbonyl).

(B) 4-phenyl- 1 -cyanoacetylpiperazine Again, the reaction conditions are not considered critical 5 and may be varied while still obtaining satisfactory re- To mole) of Sodlum cyafllde 111 Sults. of water was added dropwise 28.0 g. (0.11 mole) of 1- A tetrazole is conveniently formed by reacting the phenyl-4-FhIOIOaCeiY1PiPBraZiHB in 200 of methanolamideqfitrile i di t ith n azide salt of a mono- 10 The solution was then heated on a steam bath for 4 hours valent Cation or hydrazoic acid. Examples of Such an and filtered while hot to remove sodium chloride. The azide salt include lithium azide, sodium azide, potassium methanol e Concentrated in vacuo leaving a tan Solid azide, ammonium azide and Substituted ammonium The tan solid was recrystallized from a methanol, chloroazides. For this reaction it is desirable to utilize a suitform and ether mixture giving of Product melting able solvent and catalyst. For the solvent there may be 15 at 130-132 C. used any organic solvent which will facilitate the reac- C1101, tion, that is, any ionizing solvent in which the reactarlits max. are soluble. Dimethylformamide (DMF), for examp e, is a suitable solvent. For a catalyst it is preferred to use 2260 1 untrue) 1660 1 (amlde carbonyl) an ammonium compound such as ammonium chloride or (C) 4-phenyl-1-(S-tetrazolylacetyl) piperazine an amine hydrochloride. Reaction conditions are not T 80 I critical, although refluxing of the reaction mixture for pipgazline s 7 5 i igip iwis gdd d 5????302 an extended Period of for example betwesn about mole) of sodium azide and 4.8 g. (0.09 mole) of am- 6 t0 24 hours, has been found advalltageous' monium chloride. The mixture was then heated in a wax .tetrazole formed by h nng closure reacted 25 bath at 125130 C. with stirring for 6 hours. The DMF Wlth L1A1H4 to reduce the/Fund? funcuon- Dry f was concentrated in vacuo and a brown solid remained dfofufan is beneficlany used as a Solvent m which was recrystallized twice from a methanol and step. This reaction is carried out at elevated temperatures, DMF mixture Yield 55 C. preferably with reflux, for periods in excess of about 6 Analysis calcd for C13H16N6O (percent): c 57.34. hours- The desired tetrazole may be concentrated and H 5.92' N 30.87. Found (percent): 0 56981 1 593- recrystallized at this point or an acceptable salt formed 3091. i i in an additional step.

The invention will be further described in the follow- (D) 5 [2 (4 phenyl l piperazyl)ethyl] ing example which illustrates the preparation of a specific tetmzole hydrochloride tetrazole derivative according to the synthetic process of this invention. The invention is not to be construed as To 5 of lithium aluminum hydride i 100 1 f m t in scope y this example, as it apparent dry THF was added 6.0 g. (0.022 mole) of 4-phenyl-1- that nu Other Compounds y be slmllarly P (S-tetrazolylacetyl)piperazine in 50 ml. of THF with pared with this novel Process Without departing from the stirring. The reaction mixture was then refluxed for 6 invention. hours. Excess lithium aluminum hydride was destroyed by adding 2 ml. of a 10% aqueous THF solution, 2 ml. of EXAMPLE-'5'[2'(4'PHENYL'1'PIPERAZYL) 20% sodium hydroxide, and 6 ml. of water. The solution ETHYIlTETRAZOLE was filtered and the filtrate was concentrated in vacuo leaving a tan solid. A hydrochloride salt was prepared (A) 4'pheny1l'chloroacetylplperazme by adding excess 2.8 N HCl in isopropyl alcohol to the To 32.4 g. (0.20 mole) of phenylpiperazine in 150 ml. free base formed above in methanol. Upon addition of of benzene was added ml. of 20% sodium hydroxide ether a solid formed which was recrystallized twice from and 22.5 g. (0.20 mole) of chloroacetylchloride dropan aqueous methanol ether mixture. Yield 4.5 g., M.P. wise with stirring at about 0 C. After the addition was 206207 C. complete, the solution was stirred for 3 hours at about 50 Analysis.-Calcd. for C H ClN (percent); C. 52.98; 010 C. The layers were separated and the benzene H, 6.50; N, 28.51. Found (percent): C, 52.66; H, 6.61; layer was washed with water and dried over MgSO The N, 28.57. benzene was concentrated in vacuo leaving a solid mate- Other compounds which can be similarly prepared are rial which was filtered and washed with ether. Yield 28.0 r shown in Table I with their physical and chemical characg., M.P. 7475 teristics.

TABLE I Analysis Melting Calculated Found Cornpd. point, No. Chemical name and structure 0. Formula C H N C H N 1 5[2-((4-phcnyl-l-plperazyl)ethyl] tetrazolc dihydrochloride 200-201 CnHmNmHCl 47.2 6.05 25.4 47.2 6.31 25.6

N N (dec) Q e l -N N(CH2)z-C .2HCI

2 5-[2-(4-p-fluorophcnyl-l-piperazyl)ethyl]tetrazole 194-196 CHHHFNMHCI 44.7 5. 45 25.1 44.7 5.03 23.8

(dec.) 44.3 5.49

TABLE I-Continued Analysis Melting Calculated Found Compd. point,

0. Chemical name and structure 0. Formula C H N C H N 3 -[2-(4-m-trifluoromethylphenyl-l-piperazyl)ethyl] 184-186 C14H17F3N02HC1 42.2 4. 76 21.0 42.3 4. 78 21.2

tetrazole dihydrochloride (dcc.)

N N(CH2)2O\ .2HC1

| NN CF; i

4 5-[3-(4-phenyl-1-piperazyl)propyl]tetrazole Rig-185) CnHzoNa 61. 76 7.35 30.88 61.61 7.22 80. 64

60. /H /N @a u 5 5-[3-( 1-111-ch1orophenyl-1-piperazyl)propyl] tetrazole 165-166 CnHmOlN 54.7 6. 27.4 54.7 6,47 27.4

/H NN Q? H NN 01 6 6 5-[4-(4phenyl-l piperazyDbutyHtetrazole trihydrochloride Mag-19;) C15HQQNQ.3HC1 45,5 6,32 21.2 45,7 6,20 21,1

Q19 N(CH2)4-O\ H01 M I IN The above description and example show that the 0 present invention provides a novel process for the synthesis of piperazylalkyl derivatives of tetrazoles and the 0X0 anfilogs thereof havmg beneficlal Pharmacolo516a1 from the solution; heating the nitrile in a solution inp p p eluding azide ions; separating a reaction product of the Moreover, with the process of this invention desirable formula: tetrazole derivatives may be synthesized from readily O available reactants in satisfactory overall yields. 1

R-N Noo.m.o What 1s clalmed 1s. 1. A process for the preparation of a compound of N=N the fofmulal from the solution and reducing the reaction product to NNH form the desired compound. H H2 2. A process according to claim 1 in which the piper- (n (n azine is acylated with a lower alkanoyl halide in the pres- N=N ence of a basic catalyst.

. 3. A process according to claim 1 in which the cyanide in which R is phenyl or substituted phenyl wherein the ions are derived from NaCN, KCN, LiCN or NHLCN substituents are chloro, fluoro or trifiuoromethyl and n is A process according to Claim 1 in which the azide an integer 9 frofn about 1 to 3 which process Comprises ions are derived from an azide salt of a monovalent mixlng a Plperazme of the formula: cation selected from lithium azide, sodium azide, potassium azide, or ammonium azide.

R-N NH 5. A process according to claim 1 in which the nitrile is reacted with sodium azide in the presence of an amwith a haloalkanoyl halide of the formula: monium chloride catalyst- 0 References Cited X0,.Hzni1-Y UNITED STATES PATENTS wherein X and Y are halogen atoms and can be the same 3037024 5/1962 PMCFH 26O 268 or difierent in the resence of a base' se aratin a rod- 3155666 11/1964 Cusll 260 268 t f th l P P g P 3,231,574 1/1966 Strycker et al 260-268 e 3,362,956 1/1968 Archer 260 268 3,417,096 12/1968 Juby 260-308 R-N N( i-CHH2rX DONALD G. DAUS, Primary Examiner from the mixture; heating the product in a solution con- US, Cl, X,R taining cyanide ions; separating a nitrile of the formula: 260-308, 544, 999 

